Multiplicity of glucocorticoid action in inhibiting allograft rejection.

Abstract:

:Glucocorticoids (GCs) are used as immunosuppressive and antiinflammatory agents in organ transplantation and in treating autoimmune diseases and inflammatory disorders. GCs were shown to exert their antiproliferative effects directly through blockade of certain elements of an early membrane-associated signal transduction pathway, modulation of the expression of select adhesion molecules, and by suppression of cytokine synthesis and action. GCs may act indirectly by inducing lipocortin synthesis, which in turn, inhibits arachidonic acid release from membrane-bound stores, and also by inducing transforming growth factor (TGF)-beta expression that subsequently blocks cytokine synthesis and T cell activation. Furthermore, by preferentially inhibiting the production of Th1 cytokines, GCs may enhance Th2 cell activity and, hence, precipitate a long-lasting state of tolerance through a preferential promotion of a Th2 cytokine-secreting profile. In exerting their antiproliferative effects, GCs influence both transcriptional and posttranscriptional events by binding their cytosolic receptor (GR), which subsequently binds the promoter region of cytokine genes on select DNA sites compatible with the GCs responsible elements (GRE) motif. In addition to direct DNA binding, GCs may also directly bind to, and hence antagonize, nuclear factors required for efficient gene expression, thereby markedly reducing transcriptional rate. The pleiotrophy of the GCs action, coupled with the diverse experimental conditions employed in assessing the GCs effects, indicate that GCs may utilize more than one mechanism in inhibiting T cell activation, and warrant careful scrutiny in assigning a mechanism by which GCs exert their antiproliferative effects.

journal_name

Cell Transplant

journal_title

Cell transplantation

authors

Almawi WY,Hess DA,Rieder MJ

doi

10.1016/s0963-6897(98)00042-6

subject

Has Abstract

pub_date

1998-11-01 00:00:00

pages

511-23

issue

6

eissn

0963-6897

issn

1555-3892

pii

S0963689798000426

journal_volume

7

pub_type

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